KR20230104767A - 모르피난 유도체 - Google Patents
모르피난 유도체 Download PDFInfo
- Publication number
- KR20230104767A KR20230104767A KR1020237022162A KR20237022162A KR20230104767A KR 20230104767 A KR20230104767 A KR 20230104767A KR 1020237022162 A KR1020237022162 A KR 1020237022162A KR 20237022162 A KR20237022162 A KR 20237022162A KR 20230104767 A KR20230104767 A KR 20230104767A
- Authority
- KR
- South Korea
- Prior art keywords
- carbon atoms
- alkyl
- moiety
- compound
- substituted
- Prior art date
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- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 374
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 154
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 124
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 39
- 239000001257 hydrogen Substances 0.000 claims abstract description 39
- 125000004429 atom Chemical group 0.000 claims abstract description 26
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 26
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 21
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 17
- 239000000470 constituent Substances 0.000 claims abstract description 17
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 13
- 125000006413 ring segment Chemical group 0.000 claims abstract description 13
- -1 methylenedioxy Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 35
- 235000019000 fluorine Nutrition 0.000 claims description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001153 fluoro group Chemical group F* 0.000 claims description 20
- 125000004423 acyloxy group Chemical group 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 17
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 238000010511 deprotection reaction Methods 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 claims description 9
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 9
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 9
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 9
- 125000000524 functional group Chemical group 0.000 claims description 9
- CVQUWLDCFXOXEN-UHFFFAOYSA-N Pyran-4-one Chemical compound O=C1C=COC=C1 CVQUWLDCFXOXEN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004442 acylamino group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 7
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 125000005325 aryloxy aryl group Chemical group 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 8
- 150000001721 carbon Chemical group 0.000 claims 5
- 125000005843 halogen group Chemical group 0.000 claims 3
- 230000000996 additive effect Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 111
- 239000012453 solvate Substances 0.000 abstract description 103
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 25
- 239000000935 antidepressant agent Substances 0.000 abstract description 20
- 230000001430 anti-depressive effect Effects 0.000 abstract description 16
- 229940125713 antianxiety drug Drugs 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 267
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 132
- 238000006243 chemical reaction Methods 0.000 description 131
- 239000000243 solution Substances 0.000 description 109
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- 230000002829 reductive effect Effects 0.000 description 101
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 85
- 238000012360 testing method Methods 0.000 description 70
- 239000002904 solvent Substances 0.000 description 65
- 238000003786 synthesis reaction Methods 0.000 description 53
- 230000015572 biosynthetic process Effects 0.000 description 50
- 238000001914 filtration Methods 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000203 mixture Substances 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 41
- 238000000034 method Methods 0.000 description 40
- 239000000126 substance Substances 0.000 description 37
- 239000007821 HATU Substances 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 229910021529 ammonia Inorganic materials 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- WKHDSWRHAWZPDQ-XYIHQMNUSA-N C1(CC1)CN1CC[C@]23[C@@H]4[C@H]5CN[C@@H]4CC[C@]2([C@H]1CC1=CC=C(C=C13)O)C5 Chemical compound C1(CC1)CN1CC[C@]23[C@@H]4[C@H]5CN[C@@H]4CC[C@]2([C@H]1CC1=CC=C(C=C13)O)C5 WKHDSWRHAWZPDQ-XYIHQMNUSA-N 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 26
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
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- 230000000694 effects Effects 0.000 description 23
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- 208000019901 Anxiety disease Diseases 0.000 description 19
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 241000700159 Rattus Species 0.000 description 19
- 229940005513 antidepressants Drugs 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 229940079593 drug Drugs 0.000 description 16
- 239000002249 anxiolytic agent Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 108700023159 delta Opioid Receptors Proteins 0.000 description 14
- 102000048124 delta Opioid Receptors Human genes 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 13
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- 230000036506 anxiety Effects 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 238000012746 preparative thin layer chromatography Methods 0.000 description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
- 208000018737 Parkinson disease Diseases 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 11
- 230000000049 anti-anxiety effect Effects 0.000 description 11
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- 238000000605 extraction Methods 0.000 description 9
- 230000036407 pain Effects 0.000 description 9
- 241000282412 Homo Species 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
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- 102000048260 kappa Opioid Receptors Human genes 0.000 description 8
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- 230000036318 urination frequency Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 108020001588 κ-opioid receptors Proteins 0.000 description 8
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
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- 238000010998 test method Methods 0.000 description 7
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 6
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- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 6
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- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 5
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
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- A61P7/10—Antioedematous agents; Diuretics
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- A—HUMAN NECESSITIES
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- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| WO2018030382A1 (ja) | 2016-08-09 | 2018-02-15 | 国立大学法人 筑波大学 | モルヒナン誘導体 |
| WO2018052114A1 (ja) * | 2016-09-16 | 2018-03-22 | 国立大学法人 筑波大学 | モルヒナン誘導体のオピオイドδ受容体アゴニスト関連疾患の治療のための使用 |
| WO2018066532A1 (ja) * | 2016-10-03 | 2018-04-12 | 学校法人 星薬科大学 | モルヒナン誘導体を含む医薬組成物及びその鎮痛剤への使用 |
| CA3147221A1 (en) | 2019-07-19 | 2021-01-28 | Nippon Chemiphar Co., Ltd. | Method for producing phenol derivative |
| AU2020318159A1 (en) | 2019-07-19 | 2022-02-10 | Nippon Chemiphar Co., Ltd. | Method for producing morphinan derivative |
| EP4206203A1 (en) | 2020-08-28 | 2023-07-05 | Nippon Chemiphar Co., Ltd. | Method for preparing morphinan derivative having diaryl ether skeleton using novel copper catalyst |
Citations (6)
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| WO2001046192A1 (fr) | 1999-12-22 | 2001-06-28 | Meiji Seika Kaisha, Ltd. | COMPOSES SPIRO UTILES EN TANT QU'AGONISTES DES RECEPTEURS DES OPIOIDES $g(d) |
| JP2006522775A (ja) | 2003-04-11 | 2006-10-05 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 置換された４−フェニル−４−’１ｈ−イミダゾール−２−イル！−ピペリジン誘導体および抗抑鬱および不安緩解活性を有する選択性非ペプチドデルタオピオイドアゴニストとしてのそれらの使用 |
| WO2008001859A1 (fr) | 2006-06-30 | 2008-01-03 | School Juridical Person Kitasato Gakuen | AGONISTE DES RÉCEPTEURS δ DES OPIOÏDES |
| WO2013035833A1 (ja) | 2011-09-09 | 2013-03-14 | 学校法人北里研究所 | モルヒナン誘導体 |
| WO2014021273A1 (ja) | 2012-07-30 | 2014-02-06 | 学校法人北里研究所 | モルヒナン誘導体 |
| WO2014136305A1 (ja) | 2013-03-08 | 2014-09-12 | 学校法人北里研究所 | モルヒナン誘導体 |
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| DE10161963A1 (de) * | 2001-12-17 | 2003-07-03 | Johannes Schuetz | 6-Aminomorphinanderivate, Herstellungsverfahren dafür und deren Verwendung |
| EP1869045A1 (en) | 2005-04-04 | 2007-12-26 | AstraZeneca AB | Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases |
| CA2698753A1 (en) | 2007-09-06 | 2009-03-12 | Array Biopharma Inc. | Pyrazolo-pyridines as tyrosine kinase inhibitors |
| RU2543484C2 (ru) | 2009-10-30 | 2015-03-10 | Янссен Фармацевтика Нв | Пиразины для использования в качестве модуляторов дельта-опиоидных рецепторов |
| US9227971B2 (en) | 2010-01-19 | 2016-01-05 | Merck Sharp & Dohme Corp. | Pyrazolo[1,5-a]pyrimidine compounds as mTOR inhibitors |
| CA2822453C (en) | 2010-12-23 | 2019-04-02 | Phoenix Pharmalabs, Inc. | Novel morphinans useful as analgesics |
| JP2014073964A (ja) | 2011-01-28 | 2014-04-24 | Kitasato Institute | モルヒナン誘導体 |
| JP6163210B2 (ja) | 2012-12-14 | 2017-07-12 | パーデュー、ファーマ、リミテッド、パートナーシップ | 窒素含有モルフィナン誘導体およびその使用 |
| WO2018052114A1 (ja) | 2016-09-16 | 2018-03-22 | 国立大学法人 筑波大学 | モルヒナン誘導体のオピオイドδ受容体アゴニスト関連疾患の治療のための使用 |
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| WO2014021273A1 (ja) | 2012-07-30 | 2014-02-06 | 学校法人北里研究所 | モルヒナン誘導体 |
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